An estimated 1 million Americans are infected with HIV and another ~50,000 are infected each year. Despite progress in the treatment of AIDS, in 2007 ~2 million people around the world died from this disease. The primary nonhuman primate model in HIV/AIDS research is the rhesus macaque which develops simian-AIDS after infection with SIV. In both humans and rhesus macaques it has been demonstrated that host genetic variation can provide resistance or susceptibility to the progression to AIDS. However, as non-natural hosts of HIV/SIV, humans and rhesus macaques have not had time to adapt specific mechanisms to prevent AIDS, and those protective genetic variants that are present in the human and macaque populations are likely relics of past selection related to other infectious diseases. In contrast, the genomes of natural hosts of SIV have co-evolved with the virus and been relentlessly shaped by natural selection to acquire robust genetic mechanisms to suppress disease progression after SIV infection. Thus, identification of those robust genetic mechanisms in a natural host SIV would reveal a proven solution for how to suppress AIDS. The goal of this R21 is to identify candidates for the genetic mechanisms that have evolved to suppress progression to AIDS in a natural host of SIV, the sooty mangabey. To do so we will characterize and compare the sooty mangabey and rhesus macaque with respect to two compelling but unexplored candidate mechanisms for the difference in disease progression after SIV infection in these two nonhuman primates: micro RNA (miRNA) expression profiles during the course of SIV infection, and differences in gene copy number between these species. Specifically, we will: 1) characterize and compare the miRNA expression profiles between SIV- infected and uninfected sooty mangabeys and rhesus macaques, and 2) use array CGH to identify genes that differ in copy number between sooty mangabey and rhesus macaque as the means to identify specific miRNAs and genes that are candidates for the genetic basis of susceptibility/resistance to the progression to AIDS in these species. In summary, a comprehensive genomic study will be used to identify candidate genetic factors that have evolved to suppress AIDS in a nonhuman primate model of this disease. PUBLIC HEALTH RELEVANCE: Nonhuman primates are a unique genetic resource for studying disease progression to AIDS. The goal of this project is to characterize and compare the genomic properties of two closely-related model species used in AIDS research as a means to identify genetic mechanisms that can suppress disease progression in HIV- infected individuals.